Definition of the natural biological significance of certain human cell surface antigens is our objective. We have studied two groups of antigens. The first is an antigen or set of closely related antigens revealed after neuraminidase treatment of intact cells. The second group is the well known HL-A antigen system. Nothing as yet is known of the biological significance of the first group of antigens. The latter group has importance for organ transplantation, but our emphasis is upon the relationship of HL-A antigens to the natural function of the human organism. We are approaching the significance of the neuraminidase revealed antigen(s) by studying the chemical nature of the antigen, its distribution on different cells, its naturally occurring autoantibody, and the in vivo distribution of neuraminidase treated cells. We are seeking the significance of HL-A antigens by investigating their frequency disturbances in different diseases. If such disturbances are found, and many have been, we can design further studies on the role of the antigen in the pathophysiology of disease.